3, 4-dicarboxy-2-furan-alkanols and derivatives thereof



Patented Oct. 24, 1950 3,4-DICARBOXY-Z-FURAN-ALKANOLS AND DERIVATIVES THEREOF Klaus Hofmann, Pittsburgh, Pa., assignor to Ciba Pharmaceutical Products, Incorporated, Summit, N. J., a corporation of New Jersey No Drawing. Application June 20, 1947,

Serial No. 756,096

8 Claims. (01. zap-e45) l 2 The present invention relates to new and useful This presently preferred procedure may be ex- 3,4-dicarboxy-Z-furan-alkanols and esters thereemplified'by the following: t of, and also to the corresponding tetrahydrofuran I I I derivatives. 3 R 00(1) The present application 1s in part a contmua- 5 R I 0:0 tion of copending application, Serial No. 511,610, 0 C J; filed November 24, 1943, now Patent 2,432,016, 1 H H December 2, 1947, which, in turn, is in part a continuation of application, Serial No. 459,674 H m (now U. S. Patent No. 2,382,418) filed September R1000 000R, R1000 000R, 25, 1942, and the invention to which the present application relates involves further developments -43 g of the inventions described in the enumerated H -R prior applications. H2 H2 A primary object of the present invention is IV V the preparation of new and particularly useful W000 000E, 3,4-dicarboxy-2-furan-alkanols of the general H H formula 6 I. 11000 00011 H (5 Ht l t l-11 VI 0 wherein R stands for a free or esterified lower alkanol group, and R stands for H, alkyl, aryl and of the correspondmg tetrahydro compounds or aralkyl. Suitable esters in this connection are of the formula aliphatic and aromatic esters such for example Ia. H000 00011 as the methyl, ethyl, propyl, phenyl and. benzyl HC-CH esters.

It is also possible to replace compound II in the foregoing reaction scheme by the corresponding 0 tetrahydrofuran compound, whereby step V VI whereinRrepresents a lower alkanol group,withis obviated- The Side chain in e -D O especial reference to those situations wherein R may h of the alkahol ester yperepres'ents butanol, .(CH2)3 CH2OH, or Suitable starting materials therefore are, on pentanol, o group the one hand, the 2-substituted furans of for- A further bj t of t invention is t prepai mula II or the corresponding tetrahydrofurans ration of new and useful derivatives of the afore- (the Variables being defined as in the preceding said 3,4-dicarboxy-2-furan-alkanols and, more P ap and, on the other hand, esters of particularly, derivatives which contain the aforeacetylene dicarboxylic acid, S c as the et yl, indicated relatively complicated side chain in the 40 ethyl, py p 'opy p yl and benzy rs- 2-position, but wherein the carboxyl groups in For the partial reduction of the intermediate the 3- and 4-positions are replaced by derivative of the formula II e following catalysts may groups, as will hereinafter more particularly apfor example, be usedi metals of the platinum peat group such as platinum, palladium or others as According t t present, invention, t More; such or on carriers, or nickel in the various forms described furan derivatives may be prepared by used for p p The Catalytic reduction reacting a Z-Substituted furan derivative 11 with of the furan e to h corresponding a r d an acetylene-dicarboxylic acid ester to produce co po y be Carried u u de p sure the complex intermediate III, which is then parand at p u es etwee 20 to 250 C. with tially hydrogenated with the aid of a suitable 5 catalysts, s p1e'nickel in neutral solucatalyst to form the compound IV. The latter, tion or a metal of the plat num group n acid on distillation, loses one "molecule of ethylene, solution. and forms the corresponding 2-substituted furan- The new compounds are useful for the prepadicarboxylic jester V which, by catalytic hydroration of'substances which are valuable for therapeutic purposes or as intermediates in the progenatiomfmaibe converted into the corresponding saturated'ahalcgue VI.

duction of such substances.

Example 1 A mixture of 77.4 parts by weight of Z-furanpr'opanol and 105 parts by weight of diethyl acetylene dicarboxylate is heated on a steam-bath for twelve hours. The resulting addition compound is dissolved in 300 parts by volume of ethyl acetate and is hydrogenated in the presence of 14 parts by weight of a palladium-on-barium sulfate catalyst until one mol of hydrogen is absorbed. The catalyst is removed by filtration, the ethyl acetate removed in vacuo, and the residue decomposed in vacuo at 190-200 C. and 12 mm. pressure and then distilled; 119.6 parts by weight of 3,4-dicarbethoxy-2-furanpropanol is obtained as an oil which boils at 146-152 C. at 0.02 mm.

A solution of 119.6 parts by weight of the above 1 3,4-dicarbethoxy-2-furanpropanol in 710 parts by volume of methanol and 355 parts by volume of 5-normal potassium hydroxide is refluxed for five hours, after which the methanol is removed in vacuo. The residue is diluted with water, acidifled with concentrated hydrochloric acid, and the I resulting crystals collected, washed with water, and dried over phosphorus pentoxide in vacuo. The 3,4-dicarboxy-2-furanpropanol, 90.1 parts by weight is recrystallized from a mixture of ethyl acetate and methanol and melts at l61l62 C.

A mixture of 61.5 parts by weight of the above 3,4-dicarboxy-2-furanpropanol in 255 parts by volume of dry pyridine and 148 parts by Volume of acetic anhydride is heated on a steam-bath until all of the solid is dissolved, and the resulting solution is kept at room temperature for twelve hours. The solvents are removed in vacuo, the residue is acidified to Congo red with concentrated hydrochloric acid, and the crude acetate is Example 2 Fifty parts by weight of z-furanbutanol and 67 parts by weight of diethyl acetylene dicarboxylate are heated on the steam-bath over night. The reaction mixture is dissolved in 300 parts b volume of ethyl acetate and hydrogenated at room temperature and atmospheric pressure in the presence of 8 parts by weight of a palladium-onthree hours. The methano1 is removed in vacuo, the residue diluted with water and cooled in an ice-bath. Concentrated hydrochloric acid is added slowly with constant stirring until the mixture is acid to Congo red. After refrigeration over night, the crystals are collected, washed with ice water, and dried over phosphorus pentoxide in vacuo. The crude material is recrystallized from a mixture of methanol and ethylacetate; melting point 126-127 C.

To 57.5 parts by weight of 3,4-dicarboxy-2- furan-butanol in 235 parts by volume of dry pyridine are added slowly 150 parts by volume of acetic anhydride. After standing over night, the solvents are removed in vacuo, the residue is dissolved in ethyl acetate and the solution washed with 2-normal hydrochloric acid and water, and extracted with several portions of 10 per cent sodium bicarbonate. The combined bicarbonate extracts are acidified with concentrated hydrochloric acid to Congo red and the desired compound re-extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulfate, and the solvent removed in vacuo. The crystalline residue of 3,4-dicarboxy-2-furan-butanol acetate is repeatedly washed with petroleum ether (boiling point 30-60 C.) and dried over phosphorus pentoxide; 61.3 parts by Weight of the substance are obtained.

The 2-furanbutanol used in this example is obtained as follows:

To a three-neck flask, equip ed with a dropping funnel and a stirrer with a mercury seal, are added 300 parts by weight of 2-furanpropanol and 312 parts by Weight of dimethyl aniline. The flask is cooled in an ice-salt-bath, and 306 parts by Weight of thionyl chloride in 180 parts by volume of dry chloroformare added dropwise with stirring. The inside temperature is kept at 0-10 C. throughout the operation. After addition of the thionyl chloride the mixture is stirred for one hour, poured on crushed ice, and extracted with three 300 parts by volume portionsof chloroform. The chloroform extracts are washed with six 250 parts by volume portions of 2-normal hydrochloric acid, two portions of water, six 250 parts by volume portions of 2-normal potassium carbonate, and dried over sodium sulfate. The solvent is removed in vacuo, and the residue on distillation yields 2-furanpr0pyl chloride as'a colorless liquid which boils at 8092 C. at 13 mm.

To a solution of 71 parts by weight of Z-furanpropyl chloride in 700 parts by volume of 95 per barium sulfate catalyst until one mol of hydrogen has been absorbed. The catalyst is removed by filtration, the ethyl acetate is evaporated in vacuo and the residue heated to 190-200 C., at 16 mm. until the evolution of ethylene has ceased,

cent alcohol, 36 parts by weight of potassium cyanide dissolved in 75 parts by volume of water are added, and the mixture refluxed for 22 hours. The solution is concentrated to one-third of its volume, 215 parts by volume of 5-normal potassium hydroxide are added, and refluxing is continued for 9 hours. Most of thealcohol is removed by distillation'and theremaining alkaline solution is extracted with ether, to remove neutral substances. It is then acidified with 18-normal sulfuric acid to Congo red" and again extracted with ether. The ether extracts are washed with water, dried over sodium sulfate,

and the ether removed on the steam-bath. The

' residue, on distillation, yields Z-fura'nbutyricacid as'a colorless liquid which boils at 9 4-ll7 C. at .03 mm. I A solution of 1'15 parts byweight ofthejlaste named acid in 1500 parts byvolume of absolute volume of methanol and 250 parts by volume of ethyl alcohol containing 40 parts by weight of'dry H01 gas is allowed to tand at room temperature overnight. The alcohol. is; removed vacuo, the residue is poured on cracked ice and-theorganic material extractedwith ether. The ethereal solution is washed with water and 2-normal potassium carbonate, dried over sodium sulfate, and the ether evaporated. Distillation of the residue gives the desired ester as a colorless liquid hi h boi at, 1. 91 2." and 2. I

4 tions? 3. ta s b W gh o h liu anbu y sa e: an 2 Pa i eish f phe o in 209 parts vo of a tea ohQ is addedap d y to 6.0. p ts b e g o sod u Ame ie? al ohol -9 Paris by mime). .israd .S Q IY and the x u s mflux d unt a o the sodium. has dissolved. The solution is cooled, 200 parts by volume of water-are added and refiuxing is. continuedfor. anadditional hour. Most of the alcohol is then removed by-stearn distillation, and the aqueous residue is, cooled and extracted with three portions of ether. The ether extracts of two such runs are combined, washed with water, dried over sodium sulfate, and the ether is removed on the steam-bath. Distillation of the residue yields 2-furanbutanol as a colorless liquid which boils at 1 -15- 117 C. at 18 mm. 7 i v Example 3 A mixture or 30.8 parts by'weight of r m- 2) n-pentanol' and 37.6 parts by weight of diethyl acetlylene dicarboxylate is heated on the steambath for-6 hours, and the-resulting viscous addition'compound is dissolved in-200 parts'by' vol ume of ethyl, acetate,and hydrogenated in the presenceof a palladium catalyst until 5700 parts by volume of hydrogen have been absorbed. The catalyst is removed by filtration and the partially hydrogenated material isdecomposed into ethylene and 3,4-dicarbethoxy-furan-(Z)-n-pentanol which purifiedby distillation. Boiling point 174-175 C. at 0.01 mm.

1.5 parts by weight of'the above 3,4-dicarbethoxy-furan-(2) -n-pentanol are refluxed for 3 hours with 4 parts by volume of 5-normal KOH and 8 parts by volume of methanol. The solution, isi then congentrated' to a small volume in vacuo and acidified to Congo red with concentrated HCl. The resultant crude 3,4-dicarboxyfuran-(2)-n-pentanol is purified by crystallization from ethyl acetate and melts at 124-126 C.

By proceeding in a manner analogous to that set forth in the last paragraph of Example 1, the afore-obtained 3,4 dicarboxy-furan-(2) n-pentanol can be converted to the corresponding acetate or other ester.

The furyl-(Z) -n-pentanol used in this example is prepared as follows:

46.? parts by weight of furyl-(2) -n-valeric acid are dissolved in 500 parts by volume of 4% abso. lute alcoholic HCl and the solution is kept at room temperature for 12 hours. The solution is then concentrated to a small volume in vacuo and the ester isolated in the usual manner. The ester is obtained as a colorless liquid which boils at l30-133 C. at 16 mm.

' parts by weight of the above ethylester of furyl-(2) -n-valeric acid are dissolved in 100 parts by volume of absolute alcohol and this solution is rapidly added to 30 parts by weight of sodium. 200 parts by volume of absolute alcohol are gradually added and the mixture is heated on the steam-bath until all of the sodium is dissolved. The solution is cooled and the sodium ethylate is decomposed by the addition of 100 parts by volume of water. The strongly alkaline solution is refluxed for an additional hour and the alcohol i Example 4 2.0 parts by weight of sgi-dicarbethoxy -furan- (2 ):n-pentanol are dissolvedin 200 parts by volume ofethyl alcohoLand are hydrogenated over npentanoljare dissolved in 100 parts by volume of glacial acetic acid and are hydrogenated in.

aRaney nickelcatalyst at an initial pressure of 1900 pounds and a temperature of l70-1-80f C. for 3 hours. The catalyst is filtered oil and the alcoholremoved in-vacuo. The oily residue is dissolved in ether, washed with o z-normal sodium carbonate and water and dried over sodium sulfate. The ether is removed on the steambath and the residue distilled in vacuo. The hydrogenated esters boil at 175480 C. at 0.02 mmand have the following constants: 11 :1102; n =1.466,0..

Example 5 'l'0'parts by weight of 3,4 1-dicarboxy-furan-(2)- the presence "of a palladium catalyst at 1100 pounds initial pressure and a temperature oi -150 C. for several hours. The catalyst is 20 parts by volume of 1-normal KOHand'is kept" at room temperature. for 12 hours. The solution is then acidified to Congo red with concentrated hydrochloric acid and the reduced acids are isolated by other extraction. The acids are esterified with 100 parts by volume of 5% ethanolic HCl and the esters are distilled in vacuo. Boiling point l68-1'70'C.at '0.02-mm. I I

Havingthus'disclosed the invention, what is claimediis: 1

1. A compound of the formula wherein R stands for a member of the group consisting of free and esterified lower alkanol groups, R stands for a member of the group consisting of hydrogen, alkyl, aryl and aralkyl, and X is a nucleus of the group consisting of the furan and tetrahydrofuran nuclei, the R'OOC radicals being attached in the 3,4-positions and the R-group in the 2-position of the said nucleus.

2. A compound of the formula EO/ILKBHMCEUOH 3. A compound of the formula HOOC coon lQJ-(CHDlCHiOH 4. A compound of the formula HOOC OOOH KOJ WEDMOHQOH.

5. In a process for the preparation of 8.500111- pound of the formula wherein R stands fora member of the group consisting, of free and esterified lower alkanol groups, R stands for a member of the group consisting of hydrogen, alkyl, aryl and aralkyl, and X is a nucleusof the group consisting of the furan and tetrahydrofuran nuclei, the ROOC radicals being attached in the 3,4- positions and the R-group in the 2-position of the said nucleus, the steps of reacting a compound of the formula wherein R has the precedingly-recited significance, with an acetylene dicarboxylic acid ester, partially hydrogenating the reaction product, and heating the resultant partially hydrogenated product to decompose the same into ethylene and the corresponding 3-COOR'-4-COOR-furan- (2)-R. compound, and recovering the latter, R and R having in the last-named compound the precedingly-recited significances.

6. A processfor the preparation of a compound .of the formula HsCnOOC' 00002115 J'qonmcmon which comprises the steps of reacting furyl-(Z) n-pentanol with diethyl acetylene dicarboxylate, partially hydrogenating the reaction product, heating the resultant partially hydrogenated product to decompose the same into ethylene and 3,4-dicarbethoxy-furan-(2) -n-pentanol, and recovering the latter.

"7. A process for the preparation of a compound of the formula HOOC COOH LO i (CH2)4CH2OH HOOC COOH L 1 cinnamon which comprises the steps of reacting 2-furanbutanol with diethyl acetylene dicarbo'xylate, partially hydrogenating the reaction product, heating the resultant partially hydrogenated product to decompose the same into ethylene and 3,4-dicarbethoxy-2-furanbutanol, recovering the latter and converting the same into the corresponding 3,4-dicarboxy compound with the aid of a hydrolyzing agent.

KLAUS HOFMANN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,382,418 Hoffman Aug. 14, 1945 OTHER REFERENCES Richter, Textbook of Organic Chemistry, p.

1'25, John Wiley 8: Sons. Inc., New York, 1938.

Certificate of Correction Patent No. 2,527,421 October 24, 1950 KLAUS HOFMANN It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows;

Column 2, lines 3 to 5, inclusive, Formula III, for that portion reading n'ooc coon' n'ooo 000R J reed I I column 5 line 30, for acetlylene read acetylene; and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 26th day of December, A. D. 1950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. A COMPOUND OF THE FORMULA 